US4010282A - Anti-arrhythmic agents - Google Patents
Anti-arrhythmic agents Download PDFInfo
- Publication number
- US4010282A US4010282A US05/590,156 US59015675A US4010282A US 4010282 A US4010282 A US 4010282A US 59015675 A US59015675 A US 59015675A US 4010282 A US4010282 A US 4010282A
- Authority
- US
- United States
- Prior art keywords
- sup
- dibenzyl
- arrhythmic
- sub
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000003416 antiarrhythmic agent Substances 0.000 title abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 4
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000000203 mixture Substances 0.000 abstract description 8
- 230000001225 therapeutic effect Effects 0.000 abstract description 7
- 150000007513 acids Chemical class 0.000 abstract description 3
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 238000007911 parenteral administration Methods 0.000 abstract 1
- 239000000546 pharmaceutical excipient Substances 0.000 abstract 1
- 229940124531 pharmaceutical excipient Drugs 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 230000003288 anthiarrhythmic effect Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- XFSBVAOIAHNAPC-XTHSEXKGSA-N 16-Ethyl-1alpha,6alpha,19beta-trimethoxy-4-(methoxymethyl)-aconitane-3alpha,8,10alpha,11,18alpha-pentol, 8-acetate 10-benzoate Chemical compound O([C@H]1[C@]2(O)C[C@H]3[C@@]45C6[C@@H]([C@@]([C@H]31)(OC(C)=O)[C@@H](O)[C@@H]2OC)[C@H](OC)[C@@H]4[C@]([C@@H](C[C@@H]5OC)O)(COC)CN6CC)C(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-XTHSEXKGSA-N 0.000 description 4
- XFSBVAOIAHNAPC-UHFFFAOYSA-N Aconitin Natural products CCN1CC(C(CC2OC)O)(COC)C3C(OC)C(C(C45)(OC(C)=O)C(O)C6OC)C1C32C4CC6(O)C5OC(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 229940039750 aconitine Drugs 0.000 description 4
- STDXGNLCJACLFY-UHFFFAOYSA-N aconitine Natural products CCN1CC2(COC)C(O)CC(O)C34C5CC6(O)C(OC)C(O)C(OC(=O)C)(C5C6OC(=O)c7ccccc7)C(C(OC)C23)C14 STDXGNLCJACLFY-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 206010015856 Extrasystoles Diseases 0.000 description 3
- 206010022998 Irritability Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 3
- 125000005263 alkylenediamine group Chemical group 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000297 inotrophic effect Effects 0.000 description 3
- 230000036279 refractory period Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000008131 Ventricular Flutter Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- REYFJDPCWQRWAA-UHFFFAOYSA-N antazoline Chemical compound N=1CCNC=1CN(C=1C=CC=CC=1)CC1=CC=CC=C1 REYFJDPCWQRWAA-UHFFFAOYSA-N 0.000 description 2
- 229960002469 antazoline Drugs 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 230000036747 functional refractory period Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229960004215 prajmaline Drugs 0.000 description 2
- UAUHEPXILIZYCU-ALHOSYKFSA-N prajmalium Chemical compound CN([C@H]12)C3=CC=CC=C3[C@]11C[C@@H]3[N@@+](CCC)([C@@H]([C@H]4CC)O)[C@H]2C[C@@H]4[C@@H]3[C@H]1O UAUHEPXILIZYCU-ALHOSYKFSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000033764 rhythmic process Effects 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000009923 sugaring Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 206010047302 ventricular tachycardia Diseases 0.000 description 2
- BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical compound NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 description 1
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- WXDYPNCEAYJOSS-UHFFFAOYSA-N 1-(4-chlorophenyl)-n-[3-[(4-chlorophenyl)methylideneamino]propyl]methanimine Chemical compound C1=CC(Cl)=CC=C1C=NCCCN=CC1=CC=C(Cl)C=C1 WXDYPNCEAYJOSS-UHFFFAOYSA-N 0.000 description 1
- DEAODABWBHQGNS-UHFFFAOYSA-N 1-N,2-N-bis[(3-chlorophenyl)methyl]propane-1,2-diamine Chemical compound ClC=1C=C(CNCC(C)NCC2=CC(=CC=C2)Cl)C=CC1 DEAODABWBHQGNS-UHFFFAOYSA-N 0.000 description 1
- PYEMDCFPLHZFLF-UHFFFAOYSA-N 1-N,2-N-bis[(3-methoxyphenyl)methyl]propane-1,2-diamine Chemical compound COC=1C=C(CNCC(C)NCC2=CC(=CC=C2)OC)C=CC1 PYEMDCFPLHZFLF-UHFFFAOYSA-N 0.000 description 1
- NXKOMEFKYPRZFH-UHFFFAOYSA-N 1-N,2-N-bis[(4-chlorophenyl)methyl]propane-1,2-diamine Chemical compound ClC1=CC=C(CNCC(C)NCC2=CC=C(C=C2)Cl)C=C1 NXKOMEFKYPRZFH-UHFFFAOYSA-N 0.000 description 1
- JFXNGDBYCMCGLI-UHFFFAOYSA-N 1-N,2-N-bis[(4-methoxyphenyl)methyl]propane-1,2-diamine Chemical compound COC1=CC=C(CNCC(C)NCC2=CC=C(C=C2)OC)C=C1 JFXNGDBYCMCGLI-UHFFFAOYSA-N 0.000 description 1
- NADLSYHUPNECSA-UHFFFAOYSA-N 1-n,2-n-dibenzylpropane-1,2-diamine Chemical compound C=1C=CC=CC=1CNC(C)CNCC1=CC=CC=C1 NADLSYHUPNECSA-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 229930008564 C01BA04 - Sparteine Natural products 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- SLRCCWJSBJZJBV-UHFFFAOYSA-N alpha-isosparteine Natural products C1N2CCCCC2C2CN3CCCCC3C1C2 SLRCCWJSBJZJBV-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- -1 lithium aluminum hydride Chemical compound 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- VYFQGLQFOKTBIT-UHFFFAOYSA-N n,n'-bis[(4-chlorophenyl)methyl]propane-1,3-diamine Chemical compound C1=CC(Cl)=CC=C1CNCCCNCC1=CC=C(Cl)C=C1 VYFQGLQFOKTBIT-UHFFFAOYSA-N 0.000 description 1
- IXBTYWVCTCYLJR-UHFFFAOYSA-N n,n'-dibenzylbutane-1,4-diamine Chemical compound C=1C=CC=CC=1CNCCCCNCC1=CC=CC=C1 IXBTYWVCTCYLJR-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- AOHJOMMDDJHIJH-UHFFFAOYSA-N propylenediamine Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229960001945 sparteine Drugs 0.000 description 1
- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical compound C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to methods for treating arrhythmia with N,N'-dibenzyl alkylene diamines and to therapeutic compositions containing such compounds as an active ingredient.
- the anti-arrhythmic agents heretofore used in therapy are accompanied by side effects, such as a negative influence on the contractile force of the heart, so that the use of these preparations is not without problems and involves a certain weighing of risks [cf., for example, Muertz et al., Med. Mschr. 24, 239-245 (1970) and Bleifeld et al., Dtsch. Med. Wschr. 96, 671-680 (1971)].
- anti-arrhythmic agents which have a larger margin of safety between a dose which has an anti-arrhythmic effect and a dose having a negative inotropic effect, i.e., to develop agents which exhibit a greater therapeutic breadth than, for example, the well known substances such as antazoline, lidocaine, or N-propylajmaline.
- the present invention relates more in particular to therapeutic agents which contain alkylene diamine compounds of the formula: ##STR2## wherein A, B, D, and E are the same or different and are hydrogen, chlorine, or methoxy, and wherein n is 2, 3, or 4, or their salts with physiologically-tolerable acids.
- materials such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, malonic acid, succinic acid, maleic acid, citric acid, tartaric acid, lactic acid, and diamido sulfonic acid are exemplary.
- alkylene diamine derivatives which for the most part are known in the art, can be prepared by reacting an ⁇ , ⁇ -dihaloalkane with benzylamine, which latter may be substituted, or by reacting an ⁇ , ⁇ -diaminoalkane with benzyl chloride, which may be substituted, or by reducing an ⁇ , ⁇ -di-(benzylideneamino)-alkane, which latter may also be substituted in the benzene rings.
- the reaction of the amines with the halides can take place in the conventional manner in the presence or absence of a solvent.
- Suitable solvents are, for example, inert hydrocarbons. It is particularly advantageous to use an excess of the amine component as the solvent.
- the reaction can be carried out at temperatures from about 40° to about 250° C., preferably between 70° and 140° C.
- the isolation of the reaction product suitably follows by distillation. It is recommended to convert the free bases so obtained into their salts which, in case it is necessary, can be further purified by recrystallization.
- the reduction of dibenzylidene compounds can take place with the usual reducing agents such as platinum/hydrogen, lithium aluminum hydride, or sodium borohydride.
- the evidence of the anti-arrhythmic effect of the new compounds can be demonstrated on experimental animals by determination of the functional refractory period of the left auricle of the guinea pig using paired electrical stimulation according to the method of W. C. Jovier, J. Pharmakol. Exp. Therap. 148, 100-105 (1965).
- the numerous anti-arrhythmic agents, of different chemical structure and different therapeutic points of attack in man, heretofore used in therapy are all characterized by a lengthening of the functional refractory period.
- the method additionally permits determining the effects of the substance on the contractile force of the heart muscle [Reuter and Heeg, Naunyn-Schmiedeberg's Arch. Pharmak.
- Table 2 summarizes the good anti-arrhythmic efficacy of the diamines of the invention.
- the N,N'-dibenzyl propylene diamine of Table 1 is also contained in Table 2.
- the anti-arrhythmic effect of the diamines could also be confirmed in intact research animals with an experimentally-induced disturbance of the heart rhythm. If rats are continuously infused intravenously with aconitine, severe disturbances in the heartbeat sequence, such as extrasystoles, ventricular tachycardia, and ventricular flutter, which eventually lead to the death of the experimental animal, can be detected in an electrocardiogram. By a pre-treatment with the new pharmaceutical agents, the appearance of these threatening disturbances of the heart rhythm can be hindered or, on continuous administration of aconitine, can be considerably delayed.
- Table 3 shows the results of tests on N,N'-dibenzyl propylene diamine.
- the ED 25 and ED 50 are the intravenous or oral doses in mg/kg that permit a 25 percent or 50 percent increase in the dosage of aconitine administered, versus the aconitine control, until the occurrence of extrasystoles, ventricular tachycardia, and ventricular flutter.
- This Table also shows the superior effect of the new pharmaceuticals, for example N,N'-dibenzyl propylene diamine-1,3, which can be administered parenterally as well as orally.
- the alkylene diamine derivatives and their salts with physiologically-tolerable acids may be administered orally and parenterally.
- the dose for intravenous or intramuscular administration is about 0.1-2.0 mg/kg per day and about 1-10 mg/kg per day for oral use.
- the well known galenic dosage unit forms are suitable, such as tablets, dragees, capsules, and solutions.
- 35.8 g of 1,3-dibromopropane are added dropwise to 100 g of 3-chlorobenzylamine with stirring at 90°-100° C. The mixture is then stirred for one hour at 130°-140° C. After cooling, a solution of 30 g of sodium hydroxide in 400 ml of water is added dropwise and then the mixture is extracted four times with 200 ml portions of diethyl ether. The ether extracts are dried over potassium hydroxide and concentrated. The residue is distilled in vacuum. At 166°-172° C., 0.05 mm Hg, 33.1 g of the desired compound distill over.
- the compound so obtained is dissolved in isopropanol and, for salt formation, combined with a calculated amount of maleic acid.
- Tablets are prepared in a conventional manner in a tablet press from the following composition:
- the core mass comprises 9 parts of corn starch, 3 parts of lactose, and 1 part of a 60:40 vinyl pyrrolidone-vinyl acetate copolymer ("Luviscol VA 64"), cf. Pharm. Ind. 1962, 586.
- the sugaring mass comprises 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate, and 1 part of talc.
- the dragees so prepared are subsequently coated with a coating resistant to stomach juices.
- N,N'-dibenzyl-propylene diamine-di-maleinate 50 g are dissolved in 5 liters of water, isotonically adjusted with sodium chloride, and filled into ampules holding 5 ml.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Methods of treating cardiac arrhythmia by the oral or parenteral administration of N,N'-dibenzyl-alkylene diamine compounds of the formula ##STR1##or salts thereof with pharmaceutically acceptable acids, wherein A, B, D, and E are hydrogen, chlorine, or methoxy, and n is 2, 3, or 4; therapeutic compositions containing these anti-arrhythmic agents in combination with a pharmaceutical excipient.
Description
The present invention relates to methods for treating arrhythmia with N,N'-dibenzyl alkylene diamines and to therapeutic compositions containing such compounds as an active ingredient.
The anti-arrhythmic agents heretofore used in therapy are accompanied by side effects, such as a negative influence on the contractile force of the heart, so that the use of these preparations is not without problems and involves a certain weighing of risks [cf., for example, Muertz et al., Med. Mschr. 24, 239-245 (1970) and Bleifeld et al., Dtsch. Med. Wschr. 96, 671-680 (1971)]. Thus, it is desirable to develop anti-arrhythmic agents which have a larger margin of safety between a dose which has an anti-arrhythmic effect and a dose having a negative inotropic effect, i.e., to develop agents which exhibit a greater therapeutic breadth than, for example, the well known substances such as antazoline, lidocaine, or N-propylajmaline.
It has now been found that certain alkylene diamine compounds which have not heretofore been used therapeutically are suitable for the treatment of disturbances of cardiac function.
The present invention relates more in particular to therapeutic agents which contain alkylene diamine compounds of the formula: ##STR2## wherein A, B, D, and E are the same or different and are hydrogen, chlorine, or methoxy, and wherein n is 2, 3, or 4, or their salts with physiologically-tolerable acids.
As physiologically-tolerable acids, materials such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, malonic acid, succinic acid, maleic acid, citric acid, tartaric acid, lactic acid, and diamido sulfonic acid are exemplary.
The alkylene diamine derivatives, which for the most part are known in the art, can be prepared by reacting an α,ω-dihaloalkane with benzylamine, which latter may be substituted, or by reacting an α,ω-diaminoalkane with benzyl chloride, which may be substituted, or by reducing an α,ω-di-(benzylideneamino)-alkane, which latter may also be substituted in the benzene rings.
The reaction of the amines with the halides can take place in the conventional manner in the presence or absence of a solvent. Suitable solvents are, for example, inert hydrocarbons. It is particularly advantageous to use an excess of the amine component as the solvent. The reaction can be carried out at temperatures from about 40° to about 250° C., preferably between 70° and 140° C. The isolation of the reaction product suitably follows by distillation. It is recommended to convert the free bases so obtained into their salts which, in case it is necessary, can be further purified by recrystallization.
The reduction of dibenzylidene compounds can take place with the usual reducing agents such as platinum/hydrogen, lithium aluminum hydride, or sodium borohydride.
The evidence of the anti-arrhythmic effect of the new compounds can be demonstrated on experimental animals by determination of the functional refractory period of the left auricle of the guinea pig using paired electrical stimulation according to the method of W. C. Jovier, J. Pharmakol. Exp. Therap. 148, 100-105 (1965). In this experimental arrangement, the numerous anti-arrhythmic agents, of different chemical structure and different therapeutic points of attack in man, heretofore used in therapy are all characterized by a lengthening of the functional refractory period. The method additionally permits determining the effects of the substance on the contractile force of the heart muscle [Reuter and Heeg, Naunyn-Schmiedeberg's Arch. Pharmak. 268, 323-333 (1971) and Zetler and Strubelt, Naunyn-Schmiedeberg's Arch. Pharmak. 271, 335-345 (1971)]. It is, thus, highly suitable for detecting substances having a large therapeutic breadth, i.e., with a large margin of safety between anti-arrhythmically- and negative inotropically-effective doses.
The testing of the substances employed up to 30 individual experiments in each case. For the determination of the effective dose, linear regression functions were calculated [cf. A. Lindner, Statistische Methoden, 3rd Edition, Birkhaeuser Verlag, Basel (1969)], in which the maximum percentage deviations from the starting value in a time period up to 30 minutes after addition of the test substance to the bath liquid was employed.
In column I of following Table 1, one of the new compounds and known anti-arrhythmic agents are entered. Column II gives the anti-arrhythmic effect. Column III reports the inotropic effect. The therapeutic breadth of the compounds is given in column IV. The ED25 is the effective dose which lengthens the refractory period by 25 percent or lowers the contractile force by 25 percent. It is evident from the Table that the substance of the invention is clearly superior to the known substances from the point of view of the safety margin between the desired rhythm-regularizing effect and the undesirable influence on the contractility of the heart.
TABLE I __________________________________________________________________________ II III I Anti-arrhythmic Effect Inotropic Effect IV Anti-arrhythmic (Prolongation of the (Decrease in Therapeutic Breadth Agent Refractory Period) Contractile Force) (III/II) __________________________________________________________________________ N,N'-dibenzyl-propylene- ED.sub.25 = 0.054 ED.sub.25 = 0.141 2.6 diamine-1,3 N,n-propylajmaline ED.sub.25 = 0.0037 ED.sub.25 = 0.0015 0.4 Antazoline ED.sub.25 = 0.164 ED.sub.25 = 0.094 0.6 __________________________________________________________________________
Table 2 summarizes the good anti-arrhythmic efficacy of the diamines of the invention. The N,N'-dibenzyl propylene diamine of Table 1 is also contained in Table 2.
TABLE 2 __________________________________________________________________________ Dose Anti-arrhythmic Effect (% Prolongation Mol/l of the Refractory Period) __________________________________________________________________________ N,N'-dibenzyl-propylenediamine 10.sup.-.sup.4 47 N,N'-dibenzyl-ethylenediamine 10.sup.-.sup.4 39 N,N'-dibenzyl-butylenediamine 10.sup.-.sup.4 44 N,N'-di-(m-chlorobenzyl)-propylenediamine 2 × 10.sup.-.sup.5 45 N,N'-di-(p-chlorobenzyl)-propylenediamine 10.sup.-.sup.5 37 N,N'-di-(m,p-dichlorobenzyl)-propylenediamine 10.sup.-.sup.5 26 N,N'-di-(m-methoxybenzyl)propylenediamine 5 × 10.sup.-.sup.5 40 N,N'-di-(p-methoxybenzyl)-propylenediamine 10.sup.-.sup.4 51 N,N'-di-(m,p-dimethoxybenzyl)propylenediamine 10.sup.-.sup.4 42 __________________________________________________________________________
The anti-arrhythmic effect of the diamines could also be confirmed in intact research animals with an experimentally-induced disturbance of the heart rhythm. If rats are continuously infused intravenously with aconitine, severe disturbances in the heartbeat sequence, such as extrasystoles, ventricular tachycardia, and ventricular flutter, which eventually lead to the death of the experimental animal, can be detected in an electrocardiogram. By a pre-treatment with the new pharmaceutical agents, the appearance of these threatening disturbances of the heart rhythm can be hindered or, on continuous administration of aconitine, can be considerably delayed. This experimental model of arrhythmia has already been checked for its evidentiary value using clinically tested standard therapeutic agents and is highly suitable for an experimental animal characterization of anti-arrhythmic agents [cf. Bianchi et al., Arzneim. Forsch. 18, 845-850 (1968); Haas and Busch, Arzneim. Forsch. 18, 401-407 (1968); Haas et al., Arzneim. Forsch. 21, 1392-1399 (1971); Marmo, Naunyn-Schmiedeberg's Arch. Pharmak. 269, 231-247 (1971); and Strubelt et al., Naunyn-Schmiedeberg's Arch. Pharmak. 271, 346-360 (1971)].
Table 3 shows the results of tests on N,N'-dibenzyl propylene diamine. The ED25 and ED50 are the intravenous or oral doses in mg/kg that permit a 25 percent or 50 percent increase in the dosage of aconitine administered, versus the aconitine control, until the occurrence of extrasystoles, ventricular tachycardia, and ventricular flutter.
This Table also shows the superior effect of the new pharmaceuticals, for example N,N'-dibenzyl propylene diamine-1,3, which can be administered parenterally as well as orally.
TABLE 3 __________________________________________________________________________ N,N'-DIBENZYL-PROPYLENEDIAMINE-1,3 SPARTEINE __________________________________________________________________________ i.v. p.o. i.v. Extrasystoles ED.sub.25 5.2 65.8 .sup.+) ED.sub.50 6.0 96.2 .sup.+) Ventr. Tachycardia ED.sub.25 5.3 55.4 4.4 ED.sub.50 6.2 71.6 9.6 Ventr. Flutter ED.sub.25 4.9 51.1 .sup.+) ED.sub.50 6.4 69.9 .sup.+) __________________________________________________________________________ .sup.+) no significant effect attainable
The alkylene diamine derivatives and their salts with physiologically-tolerable acids may be administered orally and parenterally. The dose for intravenous or intramuscular administration is about 0.1-2.0 mg/kg per day and about 1-10 mg/kg per day for oral use. For administration, the well known galenic dosage unit forms are suitable, such as tablets, dragees, capsules, and solutions.
A better understanding of the present invention and of its many advantages will be had by referring to the following specific examples, given by way of illustration.
35.8 g of 1,3-dibromopropane are added dropwise to 100 g of 3-chlorobenzylamine with stirring at 90°-100° C. The mixture is then stirred for one hour at 130°-140° C. After cooling, a solution of 30 g of sodium hydroxide in 400 ml of water is added dropwise and then the mixture is extracted four times with 200 ml portions of diethyl ether. The ether extracts are dried over potassium hydroxide and concentrated. The residue is distilled in vacuum. At 166°-172° C., 0.05 mm Hg, 33.1 g of the desired compound distill over.
The compound so obtained is dissolved in isopropanol and, for salt formation, combined with a calculated amount of maleic acid. The isopropanol is distilled off and the residue, comprising N,N'-di-(3'-chlorobenzyl)-propylene-1,3-diamine-di-maleinate, is recrystallized from methanol/water. m.p. = 203°-204° C.
A solution of 54.7 g of N,N'-di-(4-chlorobenzylidene)-1,3-diaminopropane in 1 liter of methanol is combined in an ice bath, with stirring, with 19.1 g of sodium borohydride. After addition of the hydride, the mixture is stirred for a further hour and then refluxed at the boiling point for an additional 1/2 hour.
After cooling, 1 liter of 10 percent sodium hydroxide is added, the mixture is shaken four times with 100 ml portions of diethyl ether, and the ether extracts are dried over sodium hydroxide. After distilling off the ether, 47 g of a colorless oil are obtained by vacuum distillation at 180° C/0.01 mm Hg. The oil has an index of refraction ND 25 = 1.5715. The di-maleinate, prepared as in part (a), melts at 219°-220° C.
Tablets are prepared in a conventional manner in a tablet press from the following composition:
70.00 mg of N,N'-dibenzyl-propylene diamine-dihydrochloride
50.00 mg of corn starch
4.50 mg of gelatin
15.00 mg of lactose
7.50 mg of talc
0.75 mg of chemically pure submicroscopically-divided silicic acid ("Aerosil")
2.25 mg of potato starch (as a 6 percent paste).
Dragees of the following composition are prepared in the usual manner:
50.00 mg of N,N'-dibenzyl-propylene diamine
85.00 mg of corn mass
80.00 mg of sugaring mass
The core mass comprises 9 parts of corn starch, 3 parts of lactose, and 1 part of a 60:40 vinyl pyrrolidone-vinyl acetate copolymer ("Luviscol VA 64"), cf. Pharm. Ind. 1962, 586. The sugaring mass comprises 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate, and 1 part of talc. The dragees so prepared are subsequently coated with a coating resistant to stomach juices.
50 g of N,N'-dibenzyl-propylene diamine-di-maleinate are dissolved in 5 liters of water, isotonically adjusted with sodium chloride, and filled into ampules holding 5 ml.
Claims (3)
1. The method of treating cardiac arrhythmia in a patient suffering therefrom which comprises orally or parenterally administrating a therapeutically effective amount of an N,N'-dibenzyl alkylene diamine compound of the formula ##STR3## or of a salt thereof with a physiologically tolerable acid, wherein A, B, D, and E are hydrogen, chlorine, or methoxy, and n is 2, 3, or 4.
2. The method as in claim 1 wherein from 0.1-2.0 mg/kg/day of said compound or salt are parenterally administered.
3. The method as in claim 1 wherein from 1-10 mg/kg/day of said compound or salt are administered orally.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2438288A DE2438288A1 (en) | 1974-08-09 | 1974-08-09 | NEW ANTIARRHYTHMICS |
DT2438288 | 1974-08-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
US4010282A true US4010282A (en) | 1977-03-01 |
Family
ID=5922788
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US05/590,156 Expired - Lifetime US4010282A (en) | 1974-08-09 | 1975-06-25 | Anti-arrhythmic agents |
Country Status (6)
Country | Link |
---|---|
US (1) | US4010282A (en) |
BE (1) | BE832121A (en) |
DE (1) | DE2438288A1 (en) |
FR (1) | FR2281106A1 (en) |
GB (1) | GB1471089A (en) |
NL (1) | NL7508325A (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4448776A (en) * | 1981-02-12 | 1984-05-15 | Karl Bucher | Method of using certain substituted aliphatic secondary amines or their salts for easing breathing |
US4645768A (en) * | 1983-01-21 | 1987-02-24 | Fisons Plc | Formulations |
WO2013184202A1 (en) * | 2012-06-08 | 2013-12-12 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Fbxo3 inhibitors |
JP2017521392A (en) * | 2014-06-16 | 2017-08-03 | ユニヴェルシテ・ドゥ・リール・2・ドロワ・エ・サンテ | Compounds, pharmaceutical compositions and their use in the treatment of neurodegenerative diseases |
US9849098B2 (en) | 2013-12-09 | 2017-12-26 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compositions and methods for treating respiratory injury or disease |
US10487076B2 (en) | 2014-12-10 | 2019-11-26 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compositions and methods for treating diseases and conditions |
-
1974
- 1974-08-09 DE DE2438288A patent/DE2438288A1/en not_active Withdrawn
-
1975
- 1975-06-25 US US05/590,156 patent/US4010282A/en not_active Expired - Lifetime
- 1975-06-26 GB GB2706775A patent/GB1471089A/en not_active Expired
- 1975-07-11 NL NL7508325A patent/NL7508325A/en unknown
- 1975-08-05 FR FR7524433A patent/FR2281106A1/en not_active Withdrawn
- 1975-08-05 BE BE158938A patent/BE832121A/en unknown
Non-Patent Citations (2)
Title |
---|
J. Med. Chem., 7(4), 500-503, (1964); vol. 8(3), (1965), 401-404. * |
J. Med. Chem., 9(3), 329-334, (1966). * |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4448776A (en) * | 1981-02-12 | 1984-05-15 | Karl Bucher | Method of using certain substituted aliphatic secondary amines or their salts for easing breathing |
US4645768A (en) * | 1983-01-21 | 1987-02-24 | Fisons Plc | Formulations |
US10369150B2 (en) | 2012-06-08 | 2019-08-06 | University of Pittsburgh—of the Commonwealth System of Higher Education | Benzathine analogs |
WO2013184202A1 (en) * | 2012-06-08 | 2013-12-12 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Fbxo3 inhibitors |
CN104684895A (en) * | 2012-06-08 | 2015-06-03 | 高等教育联邦系统-匹兹堡大学 | FBXO3 inhibitors |
JP2015520187A (en) * | 2012-06-08 | 2015-07-16 | ユニバーシティ オブ ピッツバーグ オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション | FBXO3 inhibitor |
US9359284B2 (en) | 2012-06-08 | 2016-06-07 | University of Pittsburgh—of the Commonwealth System of Higher Education | Benzathine analogs |
US11857550B2 (en) | 2012-06-08 | 2024-01-02 | University of Pittsburgh—of the Commonwealth System of Higher Education | Benzathine analogs |
US10869866B2 (en) | 2012-06-08 | 2020-12-22 | University of Pittsburgh—of the Commonwealth System of Higher Education | Benzathine analogs |
US10159674B2 (en) | 2012-06-08 | 2018-12-25 | University of Pittsburgh—of the Commonwealth System of Higher Education | Benzathine analogs |
US10307423B2 (en) | 2012-06-08 | 2019-06-04 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | FBXO3 inhibitors |
US10092526B2 (en) | 2013-12-09 | 2018-10-09 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compositions and methods for treating respiratory injury or disease |
US9849098B2 (en) | 2013-12-09 | 2017-12-26 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compositions and methods for treating respiratory injury or disease |
US10844008B2 (en) | 2014-06-16 | 2020-11-24 | Universite De Lille 2 Droit Et Sante | Compounds, pharmaceutical composition and their use in treating neurodegenerative diseases |
JP2017521392A (en) * | 2014-06-16 | 2017-08-03 | ユニヴェルシテ・ドゥ・リール・2・ドロワ・エ・サンテ | Compounds, pharmaceutical compositions and their use in the treatment of neurodegenerative diseases |
US10487076B2 (en) | 2014-12-10 | 2019-11-26 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compositions and methods for treating diseases and conditions |
US11072606B2 (en) | 2014-12-10 | 2021-07-27 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compositions and methods for treating diseases and conditions |
Also Published As
Publication number | Publication date |
---|---|
GB1471089A (en) | 1977-04-21 |
BE832121A (en) | 1976-02-05 |
DE2438288A1 (en) | 1976-02-19 |
FR2281106A1 (en) | 1976-03-05 |
NL7508325A (en) | 1976-02-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3505337A (en) | N - hydrocarbyl-substituted noratropinium,haloalkylates and o-acyl derivatives thereof | |
US4632934A (en) | Imidazole derivatives and pharmaceutical use thereof | |
US3962449A (en) | Cardioactive bispidones and bispidines | |
US3968243A (en) | Substituted guanidine compounds in the treating of arrythmias | |
US4459301A (en) | Method of treating cardiac disorders using bispidine derivatives | |
EP0282547A1 (en) | Method for controlling emesis caused by chemotherapeutic agents and antiemetic agents useful therein. | |
US4010282A (en) | Anti-arrhythmic agents | |
EP0155653B1 (en) | Substituted (azacycloalk-2-yl) iminophenols and esters thereof | |
US3637803A (en) | Alkyl methylsulfonylalkyl benzoates | |
KR100352899B1 (en) | Pharmaceuticals containing novel 3-phenylsulfonyl-3,7-diazabicyclo [3,3,1] nonan-compounds | |
US4277501A (en) | Para-nitrophenylalkylamines and pharmaceutical compositions | |
SU1609453A3 (en) | Method of producing derivatives of gidantoine | |
US3966745A (en) | Vinvamine series cycloalkyl-alkyl esters | |
US4109005A (en) | Method of increasing rate of gastric emptying with pyrrolidinylbenzamides | |
US4031216A (en) | 3-(3,4-Dialkoxy-benzyl)-3-methyl-piperazines | |
US3708598A (en) | Substituted 2,4-(omega-aminoalkoxy)phenyl imidazoles as cholesterol reducing agents | |
WO1992006955A1 (en) | Melatonin derivative having therapeutic activity in dermatology | |
US4415495A (en) | 5,6;8,9-Tetrahydro-7H-dibenz(d,f)azonines | |
US3105006A (en) | Novel nu-arylsulfonyl-nu'-(1, 2, 3, 6-tetrahydro-1-pyridyl) ureas and oral antidiabetic compositions | |
US3996360A (en) | Piperazine compounds | |
EP0280290B1 (en) | Agent having an antidepressive activity | |
JPH03167184A (en) | N-benzyltropane amides | |
US3884954A (en) | 12-Cyano-5,6,7,12-tetrahydrodibenzo{8 a,d{9 cyclooctenes | |
US4259354A (en) | Method of treating arrhythmia | |
US3855283A (en) | Levo 1-amino-3-chloro-2-propanol and acid addition salts thereof |